Method, compositions, and compounds for modulating brain excitability

ABSTRACT

Method, compositions, and compounds for modulating brain excitability to alleviate stress, anxiety, and seizure activity using certain steroid derivatives that act at a newly identified site on the gamma-ammobutyric acid/benzodiazepine receptor-chloride ionophore (GBR) complex.

This is a continuation of co-pending application Ser. No. 07/379,047,filed on Jul. 13, 1989 and which is now abandoned which is acontinuation-in-part of copending application Ser. No. 089,362 filedAug. 25, 1987, now abandoned.

BACKGROUND OF THE INVENTION

The present invention is directed to a method, compositions, andcompounds for modulating animal brain excitability via thegamma-aminobutyric acid (GABA)/benzodiazepine (BZ) receptor-chlorideionopore complex (GBR complex).

Brain excitability is defined as the level of arousal of an animal, acontinuum that ranges from coma to convulsions, and is regulated byvarious neurotransmitters. In general, neurotransmitters are responsiblefor regulating the conductance of ions across neuronal membranes. Atrest, the neuronal membrane possesses a potential (or membrane voltage)of (approximately -80 mv, the cell interior being negative with respectto the cell exterior. The potential (voltage) is the result of ion (K⁺,Na⁺, Cl⁻, organic anions) balance across the neuronal semi-permeablemembrane. Neurotransmitters are stored in presynaptic vesicles and arereleased under the influence of neuronal action potentials. Whenreleased into the synaptic cleft, an excitatory chemical transmittersuch as acetylcholine will cause membrane depolarization (change ofpotential from -80 mv to -50 mv). This effect is mediated bypost-synaptic nicotinic receptors which are stimulated by acetylcholineto increase membrane permeability to Na⁺ ions. The reduced membranepotential stimulates neuronal excitability in the form of apost-synaptic action potential.

In the case of the GBR complex, the effect on brain excitability ismediated by GABA, a neurotransmitter. GABA has a profound influence onoverall brain excitability because up to 40% of the neurons in the brainutilize GABA as a neurotransmitter. GABA regulates the excitability ofindividual neurons by regulating the conductance of chloride ions acrossthe neuronal membrane. GABA interacts with its recognition site on theGBR complex to facilitate the flow of chloride ions down a concentrationgradient of the GBR complex into the cell. An intracellular increase inthe levels of this anion causes hyperpolarization of the transmembranepotential, rendering the neuron less susceptible to excitatory inputs(i.e., reduced neuron excitability). In other words, the higher thechloride ion concentration, the lower the brain excitability (the levelof arousal).

It is well-documented that the GBR complex is responsible for themediation of anxiety, seizure activity, and sedation. Thus, GABA anddrugs that act like GABA or facilitate the effects of GABA (e.g., thetherapeutically useful barbiturates and benzodiazepines (BZs) such asValium) produce their therapeutically useful effects by interacting withspecific regulatory sites on the GBR receptor complex.

It has also been observed that a series of steroid metabolites interactwith the GBR receptor complex to alter brain excitability (Majewska, M.D. et al., "Steroid hormone metabolites are barbiturate-like modulatorsof the GABA receptor," Science, 232:1004-1007, 1986; Harrison, N. L. etal., Structure-activity relationships for steroid interaction with thegamma-aminobutyric acid-A receptor complex, J. Pharmacol. Exp. Ther.,241:346-353, 1987). Prior to the present invention, the therapeuticusefulness of these steroid metabolites was not recognized by workers inthe field due to an incomplete understanding of the potency and site ofaction. Applicants' invention relates to a pharmaceutical application ofthe knowledge gained from a more developed understanding of the potencyand site of action of certain steroid compounds.

The ovarian hormone progesterone and its metabolites have also beendemonstrated to have profound effects on brain excitability (Backstrom,T. et al., "Ovarian steroid hormones: effects on mood, behaviour andbrain excitability," Acta Obstet. Gynecol. Scand. Suppl. 130:19-24,1985; Pfaff, D. W. and McEwen, B. S., "Actions of estrogens andprogestins on nerve cells," Science, 219:808-814, 1983; Gyermek, et al.,1968, "Structure-activity relationship of some steroidal hypnoticagents," J. Med. Chem. 11:117). The levels of progesterone and itsmetabolites vary with the phases of the menstrual cycle. It has beenwell-documented that progesterone and its metabolites decrease prior tothe onset of menses. The monthly recurrence of certain physical symptomsassociated with the onset of menses has also been well documented. Thesesymptoms, which have become associated with premenstrual syndrome (PMS)include stress, anxiety, and migraine headaches (Dalton, K.,Premenstrual Syndrome and Progesterone Therapy, 2nd edition, Chicago:Chicago Yearbook, 1984). Patients with PMS have a monthly recurrence ofsymptoms that are present in premenses and absent in postmenses.

In a similar fashion, a reduction in progesterone has also beentemporally correlated with an increase in seizure frequency in femaleepileptics (i.e., catamenial epilepsy; Laidlaw, J., "Catamenialepilepsy," Lancet, 1235-1237, 1956). A more direct correlation has beenobserved with a reduction in progesterone metabolites (Rosciszewska etal., "Ovarian hormones, anticonvulsant drugs and seizures during themenstrual cycle in women with epilepsy," J. Neurol. Neurosurg. Psych.,49:47-51, 1986). In addition, for patients with primary generalizedpetit mal epilepsy, the temporal incidence of seizures has beencorrelated with the incidence of the symptoms of premenstrual syndrome(PMS) (Backstrom, T. et al., "Production of 5-alpha-pregnane-3,20-dioneby human corpus lutem," Acta Endrocr. Suppl. 256:257, 1983).

A syndrome also related to low progesterone levels is postnataldepression (PND). Immediately after birth progesterone levels decreasedramatically leading to the onset of PND. The symptoms of PND range frommild depression to psychosis requiring hospitalization; PND isassociated with severe anxiety and irritability. PND-associateddepression is not amenable to treatment by classic antidepressants andwomen experiencing PND show an increased incidence of PMS (Dalton, K.,1984, op. cit.).

Collectively, these observations imply a crucial role for progesteronein the homeostatic regulation of brain excitability, which is manifestedas an increase in seizure activity or symptoms associated withcatamenial epilepsy, PMS, and PND. The correlation between reducedlevels of progesterone and the symptoms associated with PMS, PND, andcatamenial epilepsy (Backstrom, et al., 1983, op. cit.; Dalton, K.,1984, op. cit.) has prompted the use of progesterone in their treatment(Mattson, et al., "Medroxyprogesterone therapy of catamenial epilepsy,"in Advances in epileptology: XVth Epilepsy International Symposium,Raven Press, New York, 279-282, 1984, and Dalton, K., 1984, op. cit.).However, progesterone is not consistently effective in the treatment ofthe aforementioned syndromes. For example, no dose-response relationshipexists for progesterone in the treatment of PMS (Maddocks, et al., "Adouble-blind placebo-controlled trial of progesterone vaginalsuppositories in the treatment of premenstrual syndrome," J. Obstet.Gynecol. 154:573-581, 1986; Dennerstein, et al., British MedicalJournal, 290:16-17, 1986).

BRIEF DESCRIPTION OF THE DRAWINGS

The present invention may be better understood and its advantagesappreciated by those skilled in the art by referring to the accompanyingdrawings wherein

FIGS. 1A and 1B are plots of the binding percentage of [³⁵ S]t-butylbicyclophosphorothionate vs. log concentration of alphaxalone andGABA;

FIGS. 2A and 2B are plots of the binding percentage of [³⁵ S]t-butylbicyclophosphorothionate vs. time;

FIG. 3 is a plot showing the effect of a single dosage of pentobarbitalon 5-alpha-pregnan-3-alpha-ol-20-one modulation of [³ H] flunitrazepambinding in rat hippocampal homogenates;

FIG. 4 is a bar graph of the time to onset of myoclonus vs. differentconcentrations of steroid compounds useful in the present invention; and

FIG. 5 is a plot showing the effect of progesterone metabolites andpromogesterone (progestin R5020) on [³ H] R5020 binding to theprogesterone receptor in rat uterus.

SUMMARY OF THE INVENTION

The present invention is directed to a method, compositions, andcompounds for modulating brain excitability. More particularly, theinvention relates to the use of 3-hydroxylated-5-reduced steroids andtheir derivatives, acting at a newly identified site on the GBR complex,to modulate brain excitability in a manner that will alleviate stress,anxiety, and seizure activity. Compositions and compounds effective forsuch treatment are within the scope of the invention.

The compounds used in and forming part of the invention are modulatorsof the excitability of the central nervous system as mediated by theirability to regulate chloride ion channels associated with theGABA-benzodiazepine receptor complex. Applicants' experiments haveestablished that the compounds used in and of the invention haveanti-convulsant activity similar to the actions of known anxiolyticagents such as the benzodiazepines, but act at a distinct site on theGBR complex.

The relationship of some of the compounds used in the(invention--endogenous metabolites of progesterone--to processesassociated with reproduction (estrus cycle and pregnancy) is wellestablished (Marker, R. E., Kamm, O., and McGrew, R. V., "Isolation ofepi-Pregnanol-3-one-20 from human pregnancy urine," J. Am. Chem. Soc.59, 616-618, 1937). Prior to the present invention, however, it was notrecognized how to treat disorders by modulating brain excitability.Therefore, this invention is directed to methods, compositions, andcompounds to treat disorders by modulating brain excitability.Representative disorders treated in the present invention are epilepsy,anxiety, pre-menstrual syndrome (PMS), and post-natal depression (PND).

DETAILED DESCRIPTION OF THE INVENTION

The compounds used in the invention are3-hydroxylated-5-reduced-pregnan-20-ones,5-reduced-3,21-pregnanediol-20-ones, and 5-reduced-3,20-pregnandiols andvarious ester, oxime, and thiazolidine derivatives of such compounds,which derivatives are referred to as prodrugs by those skilled in theart of pharmaceutical preparations. The expression "prodrug" denotes aderivative of a known active drug whose derivative enhances the deliverycharacteristics and the therapeutic value of the drug and is transformedinto the active drug by an enzymatic or chemical process; see Notari, R.E., "Theory and Practice of Prodrug Kinetics," Methods in Enzymology.112:309-323 (1985) and Bodor, N., "Novel Approaches in Prodrug Design,"Drugs of the Future, 6(3):165-182 (1981). It should be noted that someof the synthetic derivatives forming part of the present invention maynot be true prodrugs because of their intrinsic activity.

Our studies (Gee, K. W., et al., "GABA-dependent modulation of the Cl⁻ionophore by steroids in rat brain," European Journal of Pharmacoloqy,136:419-423, 1987) have demonstrated that the 3-hydroxylated-5-reducedsteroids used in the invention are orders of magnitude more potent thanothers have reported (Majewska, M. D., et al., 1986, op. cit. andHarrison, N. L., et al., 1987, op. cit.) as modulators of the GBRcomplex. Our in vivo experimental data demonstrate that the high potencyof these steroids allows them to be therapeutically useful in themodulation of brain excitability via the GBR complex. The most potentsteroids useful in the present invention include major metabolites ofprogesterone. These steroids can be specifically used to modulate brainexcitability in stress, anxiety, and seizure disorders. Furthermore, wehave demonstrated that these steroids interact at a unique site on theGBR complex which is distinct from other known sites of interaction(i.e., barbiturate, benzodiazepine, and GABA) where therapeuticallybeneficial effects on stress, anxiety, sleep, and seizure disorders havebeen previously elicited (Gee, K. W. and Yamamura, H. I.,"Benzodiazepines and Barbiturates: Drugs for the Treatment of Anxiety,Insomnia and Seizure Disorders," in Drugs in Central Nervous SystemDisorders, pages 123-147, D. C. Horwell ed., 1985).

Naturally occurring metabolites of progesterone that may be used in thisinvention are those having the structural formula: ##STR1## wherein: R1is a hydroxy group;

R2 is acetyl, 2-hydroxyethanonyl, or 1-hydroxyethyl;

R3 is hydrogen; and

R4 and R5 are each a methyl group.

Exemplary of synthetic derivatives of progesterone metabolites of theinvention are those having the structural formula as illustrated above(FORMULA 1) in which:

R1 is:

(1) a pharmaceutically acceptable ester ##STR2## wherein R6 is a C₁ -C₂₀straight chain, branched chain, or cyclic aliphatic radical, or aromaticradical, or heterocyclic radical, and Y is either a divalent oxygen orsulfur linkage. This ester is formed using reactions well known in theart between the hydroxyl group of the naturally occurring compoundsdiscussed above with an organic acid, acid halide, acid anhydride, orester, wherein the organic acids are for example: acetic, propionic, nand i-butyric, n and i and s and t-valeric, hexanoic, heptanoic,octanoic, nonanoic, decanoic, undecanoic, dodecanoic, cinnamic,benzylic, benzoic, maleic, fumaric, ascorbic, pamoic, succinic,bismethylenesalicylic, methanesulfonic, ethanedisulfonic, oxalic,tartaric, salicylic, citric, gluconic, aspartic, stearic, palmitic,itaconic, glycolic, p-aminobenzoic, glutamic, benzenesulfonic,cyclohexylsulfamic, and 1-methyl-1,4-dihydronicotinic; or

(2) a pharmaceutically acceptable oxime ═N--O--R7 radical wherein R7 isa C₁ -C₂₀ straight chain, branched chain, or cyclic aliphatic radical,or aromatic radical, or heterocyclic radical. The radicals are identicalto those given in the R6 definition. This oxime is formed by thereaction of a 3-oxo derivative of progesterone by methods well known tothe art with an oxyamine; or

(3) a pharmaceutically acceptable acyloxyalkyloxy ##STR3## radicalwherein R8 is a C₁ -C₂₀ straight chain, branched chain, or cyclicaliphatic radical, or aromatic radical, or heterocyclic radical. Theradicals are identical to those given in the R6 and R7 definitions. Thisacyloxyalkyloxy embodiment is formed by the reaction of the 3-hydroxygroup of the naturally-occurring compounds discussed above by methodswell known to the art with an organic acyloxyalkyl halide (1-20 carbons)or aryloxyalkyl halide, and, in particular, acetyloxymethyl halide,diacetyloxymethyl halide, or aminoacetyloxymethyl halide;

R2 is:

(1) a pharmaceutically acceptable ##STR4## wherein R9, R10, and R11individually are a C₁ -C₂₀ straight chain, branched chain, or cyclicaliphatic radical, or aromatic radical, or heterocyclic radical, or anamide ##STR5## radical wherein R15 and R16 are individually a C₁ -C₂₀straight chain, branched chain, or cyclic aliphatic radical or aromaticradical or heterocyclic radical and n=1-8. An example of a compound ofthe present invention wherein R10 is an amide is5-alpha-pregnan-3-alpha-hydroxy-21-(N,N-diethylsuccinamate-20-one. Thesecompounds are formed by reacting the 21-hydroxy metabolite ofprogesterone in accordance with methods known in the art with an alkylhalide or organic acid, such as acetic, propionic, n and i-butyric, nand i and s and t-valeric, hexanoic, heptanoic, octanoic, nonanoic,decanoic, undecanoic, dodecanoic, cinnamic, benzylic, benzoic, maleic,fumaric, ascorbic, pamoic, succinic, bismethylenesalicylic,methanesulfonic, ethanedisulfonic, oxalic, tartaric, salicylic, citric,gluconic, aspartic, stearic, palmitic, itaconic, glycolic,p-aminobenzoic, glutamic, benzenesulfonic, cyclohexylsulfamic, and1-methyl-1,4-dihydronicotinic;

(2) a pharmaceutically acceptable ##STR6## wherein R12, R13, and R14,individually are a C₁ -C₂₀ straight chain, branched chain, or cyclicaliphatic radical, or aromatic radical, or heterocyclic radical. Thesecompounds are prepared by reacting progesterone or the 20-hydroxymetabolite of progesterone with an alkyl halide or organic acid, such asacetic, propionic, n and i-butyric, n and i and s and t-valeric,hexanoic, heptanoic, octanoic, nonanoic, decanoic, undecanoic,dodecanoic, cinnamic, benzylic, benzoic, maleic, fumaric, ascorbic,pamoic, succinic, bismethylenesalicylic, methanesulfonic,ethanedisulfonic, oxalic, tartaric, salicylic, citric, gluconic,aspartic, stearic, palmitic, itaconic, glycolic, p-aminobenzoic,glutamic, benzenesulfonic, cyclohexylsulfamic, and1-methyl-1,4-dihydronicotinic in accordance with known methods in theart;

(3) a pharmaceutically acceptable thiazolidine derivative of the 20-oxoposition on progesterone having the formula: ##STR7## wherein R17 andR18 are individually a C₁ -C₂₀ straight chain, branched chain, or cyclicaliphatic radical, or aromatic radical, or heterocyclic radical, and R19and R20 are individually hydrogen or a C₁ -C₂₀ straight chain, branchedchain, or cyclic aliphatic radical, or aromatic radical, or heterocyclicradical, or ##STR8## wherein R21 is H or a C₁ -C₂₀ straight chain,branched chain, or cyclic aliphatic radical, or aromatic radical, orheterocyclic radical;

R3 is a hydroxy, keto, alkyloxy (1 to 18 carbons), aryloxy, or aminoradical;

R4 is an alkyl (preferably 1 to 18 carbons), aryl, halo (such as fluoro,chloro, bromo, or iodo), or trifluoroalkyl; and

R5 is an alkyl (preferably 1 to 18 carbons), aryl, halo (such as fluoro,chloro, bromo, or iodo), or trifluoroalkyl.

Representative alkyloxy groups for R3 include methoxy, ethoxy, propoxy,butoxy, octoxy, dodecoxy, and octadecoxy. Aryloxy groups useful as R3moieties are phenoxy, tolyloxy, and the like.

Typical alkyl groups used as R4 and R5 are methyl, ethyl, propyl, butyl,octyl, nonyl, dodecyl, t-butyl, and octadecyl. Representative arylgroups are phenyl, benzyl, tolyl, and naphthyl. Typical trifluoroalkylgroups include trifluoromethyl and trifluoroethyl.

Typical heterocyclic groups are 1-methyl-1,4-dihydronicotinic,piperidinyl, pyridinyl, furanyl, thiophenyl, and pyrazinyl.

The following examples are directed to the preparation of compoundsforming part of and used in the present invention.

EXAMPLE 1 Preparation of 3α-hydroxy-5α-pregnan-20-one

The reaction was carried out under a dry N2 atmosphere. Potassiumtrisamylborohydride solution (KS-Selectide) in THF (6cc, 5.83 mmol) wasintroduced into a three neck round bottom flask and cooled to 0° C.5α-Pregnan-3,20-dione (1.58 g, 5 mmol) dissolved in 10 ml of anhydrouschloroform was added to the cooled reducing agent. The resulting mixturewas stirred vigorously for 2 hours at 0° C. and then allowed toequilibrate to room temperature for 1 hour. The reaction was quenchedwith 3 ml of water and 7 ml of ethanol. The organoborane was oxidizedwith 5 ml of 6M NaOH and 7 ml of 30% H₂ O₂. The reaction mixture wassaturated with anhydrous potassium carbonate, and the organic layer wasseparated. The aqueous phase was neutralized with 0.1N HCl and extractedwith 20 ml of chloroform twice. The combined organic layers were driedover anhydrous MgSO₄ and the solvent removed by rotary evaporation.Acetone was added to effect crystallization to produce a yield of 33%.The product has been identified by co-migration with authentic samplesusing silica based TLC and capillary GC. Melting point is 174°-175°.Elemental analysis: Calc. C=79.19, H=10.76. Obs. C=78.86, H═10.70, NMR:200 MHz ppm delta; 0.59 (s)(CH3), 0.77 (s)(CH3). 9-2.0 (m) (CH2), 2.1(s) (CH3--C═O), 2.5 (t) (17-H), 4.02 (t) (3-H equatorial). Thepreparation method is a modification of the method shown in Gyermek etal., "Steroids CCCX. Structure-Activity Relationship of Some SteroidalHypnotic Agents," J. Med. Chem., 11:117-125 (1968).

EXAMPLE 2 Preparation of 3-substituted esters

To a given amount of 3α-hydroxy-5α-pregnan-20-one dissolved inchloroform is added a two fold excess of the various acid chlorides (forexample: acetyl, propionyl, or butyryl chloride). The reaction isrefluxed for 10 to 15 minutes followed by neutralization with 1N NaOH.Organic layers are washed with water, dried over MgSO₄, and reduced todryness with rotary evaporation. The product is recrystallized from anacetone/hexane mixture.

EXAMPLE 3 Preparation of 20-spirothiazolidine derivatives

To a given amount of 3-substituted-5α-pregnan-20-one dissolved in 50 mlof pyridine is added a four fold excess of 1-cysteine or its methylester hydrochloride. After purging the system with nitrogen gas, thereaction mixture is stirred overnight at room temperature. The excesspyridine is evaporated and the residue dissolved in 150 ml of methylenechloride and washed with water twice. The organic layer is dried overMgSO₄. After removing the methylene chloride, the residue is boiled inmethanol and filtered hot. The product is recrystallized from anacetone/hexane mixture. See U.S. Pat. No. 4,213,978.

EXAMPLE 4 Preparation of3α-[(3-pyridiniumcarbonyl)oxy]-5α-pregnan-20-one2.

Thionyl chloride (2 ml) is added to 0.7 g (5.7 mmol) of nicotinic acidand the mixture is refluxed for 3 hours. The excess thionyl chloride isremoved under reduced pressure, and 10 ml of dry pyridine is then addedto the cold residue followed by 1.44 g of 3α-hydroxy-5α-pregnan-20-one.The mixture is heated with continuous stirring at 100° C. for 4 hours.The pyridine is removed in vacuo, and 5 ml of methanol is added to theoily residue. The mixture is cooled, and the solid that crystallizes isfiltered and recrystallized from methanol-acetone to give whitecrystals. See Bodor, "Improved Delivery Through Biological MembranesXIV: Brain-specific, Sustained Delivery of Testosterone Using a RedoxChemical Delivery System," J. Pharmaceutical Sciences. 73(3): 385-389(1984).

EXAMPLE 5 Preparation of3α-[(1-methyl-3-pyridiniumcarbonyl)oxy]-5α-pregnan-20-one

To a solution of 1.0 g of3α-(3-pyridiniumcarbonyl)oxy]-5α-pregnan-20-one in 15 ml of acetone isadded 1 ml of methyl iodide, and the mixture is heated at refluxovernight. The yellow material that separates is removed by filtration,washed with acetone and crystallized from methanol-ether to yield yellowcrystals. See the Bodor article referred to in Example 4.

It will be obvious to one skilled in the art that the above describedcompounds may be present as diastereo isomers which may be resolved intod or l optical isomers. Resolution of the optical isomers may beconveniently accomplished by gas or liquid chromatography or isolationfrom natural sources. Unless otherwise specified herein, including theclaims, reference to the compounds of the invention, as discussed above,is intended to include all isomers, whether separated or mixturesthereof.

Where isomers are separated, the desired pharmacological activity willoften predominate in one of the isomers. As disclosed herein, thesecompounds display a high degree of stereospecificity. In particular,those compounds having the greatest affinity for the GABA-benzodiazepinereceptor complex are those with 3-alpha-substituted-5-alpha-pregnanesteroid skeletons. In addition, 3-alpha-substituted-5-beta-pregnaneskeletons have been demonstrated to be active. The preferred prodrugsinclude 3α-hydroxy-5α-pregnan-20-spirothiazolidine andN-methyl-nicotinyl esters of 3α-hydroxy-5α-pregnan-20-one.

The compounds of and used in the invention, that being the naturallyoccurring metabolites of progesterone and their nontoxicpharmaceutically acceptable synthetic "prodrug" forms have hithertounknown activity in the brain at the GABA-benzodiazepine receptorcomplex. The present invention takes advantage of the understanding ofthis previously unknown activity.

The compounds of the invention may be prepared by any known technique.For example, the naturally occurring metabolites of progesterone may beextracted from various animal excretion sources, e.g., urine. Suchextractions are conducted using the following steps: (i) hydrolysis ofthe urine with HCl; (ii) extraction with toluene; (iii) removal ofacidic material from the toluene extract; (iv) elimination of substancesother than pregnanediol from the neutral toluene-soluble fraction byprecipitations from ethanolic solution with dilute NaOH and with water;and (v) weighing of the purified pregnanediol obtained. See Marrian etal., "The Isolation of Pregnane-3α-ol-20-one," Biochem., 40:376-380(1947). These extracted compounds may then be chemically altered to formthe desired synthetic derivative, or used directly.

The pharmaceutical compositions of this invention are prepared inconventional dosage unit forms by incorporating an active compound ofthe invention or a mixture of such compounds, with a nontoxicpharmaceutical carrier according to accepted procedures in a nontoxicamount sufficient to produce the desired pharmacodynamic activity in asubject, animal or human. Preferably, the composition contains theactive ingredient in an active, but nontoxic amount, selected from about50 mg to about 500 mg of active ingredient per dosage unit. Thisquantity depends on the specific biological activity desired and thecondition of the patient. The most desirable object of the compositionand methods is in the treatment of PMS, catamenial epilepsy, and PND toameliorate or prevent the attacks of anxiety, muscle tension, anddepression common with patients suffering from these central nervoussystem abnormalities.

The pharmaceutical carrier employed may be, for example, either a solid,liquid, or time release (see e.g. Remington's Pharmaceutical Sciences,14th Edition, 1970). Representative solid carriers are lactose, terraalba, sucrose, talc, gelatin, agar, pectin, acacia, magnesium stearate,stearic acid, microcrystalline cellulose, polymer hydrogels and thelike. Typical liquid carriers are syrup, peanut oil, and olive oil andthe like emulsions. Similarly, the carrier or diluent may include anytime-delay material well known to the art, such as glyceryl monostearateor glyceryl distearate alone or with a wax, microcapsules, microspheres,liposomes, and hydrogels.

A wide variety of pharmaceutical forms can be employed. Thus, when usinga solid carrier, the preparation can be tableted, placed in a hardgelatin capsule in powder or pellet form, or in the form of a troche,lozenge, or suppository. When using a liquid carrier, the preparationcan be in the form of a liquid, such as an ampule, or as an aqueous ornonaqueous liquid suspension. Liquid dosage forms also needpharmaceutically acceptable preservatives and the like. In addition,because of the low doses that will be required as based on the in vitrodata disclosed herein, timed release skin patches are also a suitablepharmaceutical form for topical administration.

The method of producing anxiolytic, or anticonvulsant activity, inaccordance with this invention, comprises administering to a subject inneed of such activity a compound of the invention, usually prepared in acomposition as described above with a pharmaceutical carrier, in anontoxic amount sufficient to produce said activity.

During menses, the levels of excreted metabolites varies approximatelyfourfold (Rosciszewska, et al., op. cit.). Therefore, therapy forcontrolling symptoms involves maintaining the patient at a more uniformlevel of progesterone metabolite. Plasma levels of active and majormetabolites are monitored during pre-menses and post-menses of thepatient. The amount of the compounds, either singly or mixtures thereof,of the invention administered reflects the physiological concentrationswhich naturally occur post-menses. The route of administration may beany route that effectively transports the active compound to theGABA-benzodiazepine receptors that are to be stimulated. Administrationmay be carried out parenterally, rectally, intravaginally,intradermally, subliqually, or nasally; the dermal route is preferred.For example, one dose in a skin patch may supply the active ingredientto the patient for a period of up to one week.

The in vitro and in vivo experimental data show that thenaturally-occurring metabolites of progesterone and their derivativesinteract with high affinity at a novel and specific recognition site onthe GBR complex to facilitate the conductance of chloride ions acrossneuronal membranes sensitive to GABA (Gee et al., 1987).

To those skilled in the art, it is known that the modulation of [³⁵ S]t-butylbicyclophosphorothionate ([³⁵ S]TBPS) binding is a measure of thepotency and efficacy of drugs acting at the GBR complex, which drugs maybe of potential therapeutic value in the treatment of stress, anxiety,and seizure disorders (Squires, R. F., et al., "[³⁵S]t-Butylbicyclophophorothionate binds with high affinity tobrain-specific sites coupled to a gamma aminobutyric acid-A and ionrecognition site," Mol. Pharmacol., 23:326, 1983; Lawrence, L. J., etal., "Benzodiazepine anticonvulsant action: gamma-aminobutyricacid-dependent modulation of the chloride ionophore," Biochem. Biophys.Res. Comm., 123:1130-1137, 1984; Wood, et al., "In vitrocharacterization of benzodiazepine receptor agonists, antagonists,inverse agonists and agonist/antagonists," J. Pharmacol. Exp. Ther..231:572-576, 1984). We performed an assay to determine the modulation of[³⁵ S] TBPS as effected by the compounds of the invention and found thatthese compounds have high potency and efficacy at the GBR complex, withstringent structural requirements for such activity.

The procedures for performing this assay are fully discussed in: (1)Gee, et al., 1987 op. cit.: and (2) Gee, K. W., L. J. Lawrence, and H.I. Yamamura, "Modulation of the chloride ionopore by benzodiazepinereceptor ligands: influence of gamma-aminobutryric acid and ligandefficacy," Molecular Pharmacology, 30, 218, 1986. These procedures wereperformed as follows:

Brains from male Sprague-Dawley rats were removed immediately followingkilling and the cerebral cortices dissected over ice. A P₂ homogenatewas prepared as previously described (Gee, et al., 1986, op. cit.).Briefly, the cortices were gently homogenized in 0.32M sucrose followedby centrifugation at 1000×g for 10 minutes. The supernatant wascollected and centrifuged at 9000×g for 20 minutes. The resultant Pzpellet was suspended as a 10% (original wet weight/volume) suspension in50 mM Na/K phosphate buffer (pH 7.4)+200 mM NaCl to form the homogenate.

One hundred microliter aliquots of the P₂ homogenate (0.5 milligrams(mg) protein) were incubated with 2 nanomolar (nM) [³⁵ S]TBPS (70-110curies/millimole;, New England Nuclear, Boston, Mass.) in the presenceor absence of the naturally occurring steroids and their syntheticderivative prodrugs to be tested. The tested compounds were dissolved indimethylsulfoxide (Baker Chem. Co., Phillipsbury, N.J.) and added to theincubation mixture in 5 microliter aliquots. The incubation mixture wasbrought to a final volume of 1 milliliter (ml) with buffer. Non-specificbinding was defined as binding in the presence of 2 micromolar TBPS. Theeffect and specificity of GABA (Sigma Chem. Co., St. Louis, Mo.) wasevaluated by performing all assays in the presence of 5 micromolarGABA±(+)-bicuculline (Sigma Chem. Co.). Incubations maintained at 25° C.for 90 minutes (steady state conditions) were terminated by rapidfiltration through glass fiber filters (No. 32, Schleicher and Schuell,Keene, N.H.). Filter bound radioactivity was quantitated by liquidscintillation spectrophotometry. Kinetic data and compound/[³⁵ S]TBPSdose-response curves were analyzed by non-linear regression using acomputerized iterative procedure to obtain rate constants and IC₅₀(concentration of compound at which half-maximal inhibition of basal [³⁵S]TBPS binding occurs) values.

The experimental data obtained for this assay are also published in Gee,et al., 1987. The data discussed in this reference are shown as plots inFIGS. 1A and 1B. These plots show the effect of (+)-bicuculline onalphaxalone (1A) and GABA (1B) modulation of 2 nanomolar [³⁵ S]-TBPSbinding to rat cerebral cortex. In these FIGS, (○) represents controlwithout bicuculline; () represents 0.5 micromolar bicuculline; (□)represents 1.0 micromolar bicuculline; () represents 2.0 micromolarbicuculline; and (Δ) represents 3.0 micromolar bicuculline. In thisexperiment, the effect of (+)-bicuculline on the ability of alphaxaloneor GABA to inhibit the binding of [³⁵ S]TBPS was determined. Bicucullineis known to be directly competitive with GABA and a classical parallelshift in the dose-response curves is observed in FIG. 1B. In contrast,the steroid binding site is distinct from the GABA/bicuculline site inFIG. IA. The shift in dose-response curves induced by (+)-bicucullinewhen the inhibition of [³⁵ S]-TBPS binding is caused by alphaxalone isnot linear. This indicates that the GABA and steroid sites do notoverlap.

An assay was performed to determine the effect of pentobarbital on thedissociation kinetics of [³⁵ S]TBPS in rat cerebral cortical membranes.This assay was performed in accordance with the procedures outlinedabove. These data indicate that the site of action of the compounds ofthe invention is unique and distinct from the previously known sites ofaction for the barbiturates and the BZs. The results of the in vitroassay are shown in FIGS. 2A and 2B. The plots in FIGS. 2A and 2B showthe effect of pentobarbital, alphaxalone, or5-alpha-pregnan-3-alpha-hydroxy-20-one on the dissociation kinetics for2 nanomolar [³⁵ S]TBPS in cortical P2 homogenates. Dissociation of bound[³⁵ S]TBPS was initiated by 2 micromolar TBPS in all cases.Pentobarbital (FIG. 2A) at 30 micromolar induces a biphasic dissociationmechanism which is absent for alphaxalone (300 nanomolar) and5-alpha-pregnan-3-alpha-hydroxy-20-one (20 nanomolar) (FIG. 2B).

The kinetic rate constants and half lives obtained by this assay are setforth in Table 1. The information presented in Table 1 shows that thebarbiturate induces a shift in the half life of dissociation and theproportion of slow and rapidly dissociating components - hallmarkeffects of therapeutically useful GABA agonists, barbiturates, and BZson [³⁵ S]TBPS binding (Gee, et al., 1986; Maksay, G. & Ticku, M.,"Dissociation of [³⁵ S]t-butylbicyclophophorothionate bindingdifferentiates convulsant and depressant drugs that modulate GABAergictransmission," J. Neruochem., 44:480-486, 1985). In contrast, theprogesterone metabolite 5-alpha-pregnan-3-alpha-ol-20-one and theprogestin alphaxalone do not influence the dissociation kinetics of [³⁵S]TBPS binding. The steroid and barbiturate sites are, therefore,distinct.

                                      TABLE 1                                     __________________________________________________________________________                                Total percentage of                                      t.sub.1/2 (min)                                                                          k.sub.-1 (min.sup.-1)                                                                   specific sites                                    Conditions                                                                           S    R     S    R    S    R                                            __________________________________________________________________________    Control                                                                              50 ± 4                                                                            6 ± 1                                                                          0.0145 ±                                                                        0.131 ±                                                                         73 ± 2                                                                          30 ± 2                                                      0.0008                                                                             0.016                                                  + 30 nM Na                                                                           38 ± 3                                                                            4.4 ± 0.3                                                                      0.0186 ±                                                                        0.158 ±                                                                          61 ± 6*                                                                         48 ± 6**                                 pentobarbital     0.0015                                                                             0.013                                                  + 300 nM                                                                             67 ± 12                                                                         4.9 ± 1                                                                          0.0120 ±                                                                        0.180 ±                                                                         73 ± 4                                                                          34 ± 5                                    Alphaxalone       0.003                                                                              0.040                                                  + 20 nM                                                                              76 ± 11                                                                         6.4 ± 1                                                                          0.011 ±                                                                         0.122 ±                                                                         68 ± 3                                                                          35 ± 3                                    3a-OH-DHP         0.002                                                                              0.030                                                  __________________________________________________________________________     Significantly different from control @ *P < 0.05 and **P < 0.01 by            Student's ttest. S and R represent slowly and rapidly dissociating            components respectively.                                                 

Furthermore, 5-alpha-pregnan-3-alpha-ol-20-one does not interact withpentobarbital in the enhancement of the binding of [³ H] flunitrazepamto the BZ receptor in the cortical brain homogenates (FIG. 3) indicatingthat steroids and barbiturates do not share a common site of action. Thedata of FIG. 3 were obtained by performing an assay to determine theeffect of a single concentration of pentobarbital (1.0 millimolar) on5-alpha-pregnan-3-alpha-ol-20-one modulation of 0.25 nM [³ H]flunitrazepam ([³ H]FLU) binding to the BZ receptor in rat hippocampalhomogenates. This assay was performed in accordance with the proceduresoutlined above. Each point on the plot of FIG. 3 represents the mean+SEMof 4-6 independent determinations. The data points in both curves areexpressed as percent enhancements of [³ H]FLU binding, which is definedas the percentage of [³ H]FLU bound in the absence of5-alpha-pregnan-3-alpha-ol-20-one under the control conditions minus100%. All assays were performed in the absence of GABA.

The above data demonstrate that the compounds of and used in theinvention interact with a novel site distinct from previously definedregulatory sites on the GBR complex.

Various compounds were screened to determine their potential asmodulators of [³⁵ S]TBPS binding in vitro. These assays were performedin accordance with the above discussed procedures. Based on theseassays, we have established the structure-activity requirements fortheir specific interaction at the GBR complex and their rank orderpotency and efficacy (Table 2 below).

                                      TABLE 2                                     __________________________________________________________________________                                                     +5 μM                                                                             MAXIMAL                                                         CONTROL                                                                              GABA   INHIBI-               COMPOUND                                  IC.sub.50 (nM)                                                                       IC.sub.50                                                                            TION*                 __________________________________________________________________________    5α-PREGNAN-3α-OL- 20-ONE (EPIALLO- PREGNANOLONE)                                ##STR9##                     230    17   100                    5α-PREGNAN-3α,20- DIOL (PREGNANDIOL)                                            ##STR10##                    359    82    52                    5α-PREGNAN-3α-OL- 11,20-DIONE (ALPHAXALONE)                                     ##STR11##                   11000   264  100                    5α-ANDROSTAN-3α, 17β-DIOL                                                  ##STR12##                   15000  1000  100                    PROGESTERONE                                                                                ##STR13##                   >10.sup.5                                                                            5200  100                    5α-PREGNAN-3α-21- DIOL-11,20-DIONE                                              ##STR14##                   >10.sup.5                                                                            5500  100                    5α-ANDROSTAN-17β- OL-3-ONE                                                       ##STR15##                   >10.sup.5                                                                            18000  52                    5α-PREGNAN-3β-OL- 20-ONE (ALLO- PREGNANOLONE)                                    ##STR16##                   INACTIVE                                                                             >10.sup.5                                                                            33                    5-PREGNAN-3β-OL- 20-ONE (PREGNENOLONE)                                                 ##STR17##                   INACTIVE                                                                             >10.sup.5                                                                            30                    4-PREGNEN-11β,21- DIOL-3,20-DIONE (CORTICOSTERONE)                                     ##STR18##                   INACTIVE                                                                             >10.sup.5                                                                            21                    17β-ESTRADIOL                                                                          ##STR19##                   INACTIVE                                                                             INACTIVE                                                                             0                     CHOLESTEROL                                                                                 ##STR20##                   INACTIVE                                                                             INACTIVE                                                                             0                     __________________________________________________________________________

Experiments were also performed to determine the physiological relevanceof these interactions by measuring the ability of the compounds of andused in the invention to modulate TBPS-induced convulsions inSwiss-Webster mice. Mice were injected with various doses of the testcompounds of the invention, as indicated in FIG. 4, 10 minutes prior tothe injection of TBPS. The time to onset of myoclonus (presence offorelimb clonic activity) induced by TBPS was determined by observingeach mouse for a period of 45 minutes. Significant differences betweenthe time to onset in control mice vs. steroid-treated mice weredetermined by Student's t-test. The relative rank order potency andefficacy of these steroids in vivo were well correlated with thosevalues determined in vitro. The anticonvulsant and toxicologicalprofiles of 5α-pregnan-3α-ol-20-one (3α-OH-DHP) were determined. In theanticonvulsant screen, mice were injected with various doses of3α-OH-DHP or vehicle (dimethylsulfoxide) 10 minutes prior to theadministration of the following chemical convulsants: metrazol (85mg/kg); (+)bicuculline (2.7 mg/kg); picrotoxin (3.15 mg/kg); strychnine(1.25 mg/kg); or vehicle (0.9% saline). Immediately after the injectionof convulsant or vehicle, the mice were observed for a period of 30 to45 minutes. The number of animals with tonic and/or clonic convulsionswas recorded. In the maximal electroshock test, 50 mA of current at 60Hz was delivered through corneal electrodes for 200 msec. The ability of3α-OH-DHP to abolish the tonic component was defined as the endpoint.Sedative potential was determined by a rotorod test 10 minutes after theinjection of 3α-OH-DHP where the number of mice staying on a rotating (6rpm) rod for ≧1 minute in each of 3 trials was determined. The ED₅₀ (thedose at which the half-maximal effect occurs) dose was determined foreach screen. The acute LD₅₀ (the dose that is lethal to one half of theanimals tested) was determined by counting survivors 48 hours after theadministration of 3α-OH-DHP. The results are presented in Table 3,infra, and demonstrate that 3α-OH-DHP, in comparison to other clinicallyuseful anticonvulsants, is highly effective with a profile similar tothat of the benzodiazepine clonazepam. The sedative liability atanticonvulsant doses is low as shown by comparing the ED₅₀ values forthe rotorod test and (+)bicuculline-induced seizures. The therapeuticindex (ratio of LD₅₀ to ED₅₀) for 3α-OH-DHP is >122 when based on theED₅₀ against (+)bicuculline-induced seizures, thus indicating very lowtoxicity. These observations demonstrate the therapeutic utility ofthese compounds as modulators of brain excitability, which is incorrespondence with their high affinity interaction with the GBR complexin vitro.

                                      TABLE 3                                     __________________________________________________________________________    Anticonvulsant and acute toxicological profile of 3α-OH-DHP             and those of selected clinically useful anticonvulsants in mice.                          ED.sub.50 *                                                       Compound                                                                             RR   MES MTZ   BIC  PICRO STR LD.sub.50                                __________________________________________________________________________    3α-OH-DHP                                                                       40-100                                                                            >300                                                                              18.8 ± 1.1                                                                       4.1 ± 1.7                                                                       31.7 ± 1.1                                                                       >300                                                                              >500                                     Clonazepam                                                                           0.184                                                                              93  0.009 0.0086                                                                             0.043 NP  >6000                                    Phenobarbital                                                                        69   22  13    38   28    95  265                                      Phenytoin                                                                            65   10  NP    NP   NP    **  230                                      Progabide***                                                                         --   75  30    30   105   75  3000                                     Valproate                                                                            426  272 149   360  387   293 1105                                     __________________________________________________________________________     *All ED.sub.50 values for 3α-OHDHP include the 95% confidence           limits. The abbreviations are RR (Rotorod); MES (maximal electroshock);       MTZ (metrazol); BIC (bicuculline); PICRO (picrotoxin); STR (strychnine);      NP (no protection).                                                           **Maximum protection of 50% at 55-100 mg/kg.                                  ***The chemical convulsants in the progabide studies were administered        i.v., all data from Worms et al., Gammaaminobutyric acid (GABA) receptor      stimulation. I. Neuropharmacological profiles of progabide (SL 76002) and     SL 75102, with emphasis on their anticonvulsant spectra, Journal of           Pharmacology and Experimental Therapeutics 220: 660-671, 1982. All            remaining anticonvulsant data are from Swinyard & Woodhead, General           principles: experimental detection, quantification and evaluation of          anticonVulsants, in: Antiepileptic Drugs, D. M. Woodbury, J. K. Penry, an     C. E. Pippenger, eds., p. 111, (Raven Press, New York), 1982.            

The correlations between reduced levels of progesterone and the symptomsassociated with PMS, PND, and catamenial epilepsy (Backstrom, et al.,1983, op. cit.; Dalton, K., 1984, op. cit.) led to the use ofprogesterone in their treatment (Mattson, et al., 1984; and Dalton,1984). However, progesterone is not consistently effective in thetreatment of the aforementioned syndromes. For example, no dose-responserelationship exists for progesterone in the treatment of PMS (Maddocks,et al, 1987, op. cit.). These results are predictable when considered inlight of the results of our in vitro studies which demonstrate thatprogesterone has very low potency at the GBR complex, as seen in Table2, compared to certain metabolites of progesterone.

The beneficial effect of progesterone is probably related to thevariable conversion of progesterone to the active progesteronemetabolites. The use of specific progesterone metabolites in thetreatment of the aforementioned syndromes is clearly superior to the useof progesterone based upon the high potency and efficacy of themetabolites and their derivatives (See Gee, et al., 1987, and Table 2above).

It has also demonstrated that the compounds of and used in the inventionlack hormonal side effects by the lack of affinity of these compounds ofthe invention for the progesterone receptor (FIG. 5). The data plottedin FIG. 5 were obtained by performing assays in accordance with theprocedures outlined above to determine the effect of progesteronemetabolites and the progestin R5020 on the binding of [³ H]R5020 to theprogesterone receptor in rat uterus. All points on the plot of FIG. 5represent the mean of triplicate determinations. The following compoundsare those listed in FIG. 5: 5-alpha-pregnan-3-alpha-ol-20-one (DHP),5-alpha-pregnan-3-alpha,21-diol-20-one (Th-DOC), and5-beta-pregnane-3-alpha,20 diol (5 BETA).

While the preferred embodiments have been described and illustrated,various substitutions and modifications may be made thereto withoutdeparting from the scope of the invention. Accordingly, it is to beunderstood that the present invention has been described by way ofillustration and not limitation.

We claim:
 1. A method for modulating the excitability of the centralnervous system as mediated by the ability to regulate chloride ionchannels associated with the GABA-benzodiazepine receptor complexcomprising administering to a patient in need of such treatment acentral nervous system excitability modulating pharmaceuticallyeffective amount of a 3-hydroxylated-5-reduced neuroactive steriodcompound that activates the GABA-benzodiazepine receptor-chlorideionopore complex by attaching to a brain receptor site other than anypreviously known recognition site of said complex, but associated withand still activating said complex.
 2. The method of claim 1 wherein saidpharmaceutically effective amount is sufficient to alleviate stress insaid patient.
 3. The method of claim 1 wherein said pharmaceuticallyeffective amount is sufficient to alleviate anxiety in said patient. 4.The method of claim 1 wherein said pharmaceutically effective amount issufficient to alleviate seizure activity in said patient.
 5. The methodof claim 1 wherein said compound is a compound of the formula ##STR21##wherein R1 is selected from the group consisting of hydroxyl, ##STR22##wherein R6 and R8 are individually a C₁ -C₂₀ straight chain aliphaticradical, C₁ -C₂₀ branched chain aliphatic radical or C₃ -C₂₀ cyclicaliphatic radical, or aromatic radical, or a heterocyclic radicalselected from the group consisting of 1-methyl-1,4-dihydronicotinoyl,piperidinyl, pyridinyl, furanyl, thiophenyl, and pyrazinyl, and Y is--O-- or --S--;R2 is selected from the group consisting of acetyl,2-hydroxyethanonyl, 1-hydroxyethyl, ##STR23## wherein R9, R10 and R11individually are a C₁ -C₂₀ straight chain aliphatic radical, C₁ C₂₀branched chain aliphatic radical or C₃ -C₂₀ cyclic aliphatic radical, oraromatic radical, or a heterocyclic radical selected from the groupconsisting of 1-methyl-1,4-dihydronicotinoyl, piperidinyl, pyridinyl,furanyl, thiophenyl, and pyrazinyl, or the moiety ##STR24## wherein R15and R16 individually are a C₁ -C₂₀ straight chain aliphatic radical, C₁-C₂₀ branched chain aliphatic radical or C₃ -C₂₀ cyclic aliphaticradical, or aromatic radical, or a heterocyclic radical selected fromthe group consisting of 1-methyl-1,4-dihydronicotinoyl, piperidinyl,pyridinyl, furanyl, thiophenyl, and pyrazinyl and n is an integer of 1to 8 or R2 is selected from the group consisting of ##STR25## whereinR12, R13 and R14 individually are a C₁ -C₂₀ straight chain aliphaticradical, C₁ -C₂₀ branched chain aliphatic radical or C₃ -C₂₀ cyclicaliphatic radical, or aromatic radical, or a heterocyclic radicalselected from the group consisting of 1-methyl-1,4-dihydronicotinoyl,piperidinyl, pyridinyl, furanyl, thiophenyl, and pyrazinyl; R3 isselected from the group consisting of hydrogen, hydroxy, keto, C₁ -C₁₈alkyloxy, aryloxy and amino; and R4 and R5 individually are selectedfrom the group consisting of C₁ -C₁₈ alkyl, aryl, halo andtrifluoroalkyl.
 6. The method of claim 1 wherein said compound is acompound of the formula: ##STR26## wherein R1 is ═N--O--R7 and R7 is aC₁ -C₂₀ straight chain aliphatic radical, C₁ -C₂₀ branched chainaliphatic radical or C₃ -C₂₀ cyclic aliphatic radical, or aromaticradical, or a heterocyclic radical selected from the group consisting of1-methyl-1,4-dihydronicotinoyl, piperidinyl, pyridinyl, furanyl,thiophenyl, and pyrazinyl;R2 is selected from the group consisting ofacetyl, 2-hydroxyethanonyl, 1-hydroxyethyl, ##STR27## wherein R9, R10and R11 individually are a C₁ -C₂₀ straight chain aliphatic radical, C₁-C₂₀ branched chain aliphatic radical or C₃ -C₂₀ cyclic aliphaticradical, or aromatic radical, or a heterocyclic radical selected fromthe group consisting of 1-methyl-1,4-dihydronicotinoyl, piperidinyl,pyridinyl, furanyl, thiophenyl, and pyrazinyl, or the moiety ##STR28##wherein R15 and R16 individually are a C₁ -C₂₀ straight chain aliphaticradical, C₁ -C₂₀ branched chain aliphatic radical or C₃ -C₂₀ cyclicaliphatic radical, or aromatic radical, or a heterocyclic radicalselected from the group consisting of 1-methyl-1,4-dihydronicotinoyl,piperidinyl, pyridinyl, furanyl, thiophenyl, and pyrazinyl, and n is aninteger of 1 to 8 or R2 is selected from the group consisting of##STR29## wherein R12, R13 and R14 individually are a C₁ -C₂₀ straightchain aliphatic radical, C₁ -C₂₀ branched chain aliphatic radical or C₃-C₂₀ cyclic aliphatic radical, or aromatic radical, or a heterocyclicradical selected from the group consisting of1-methyl-1,4-dihydronicotinoly, piperidinyl, pyridinyl, furanyl,thiophenyl, and pyrazinyl; and R3 is selected from the group consistingof hydrogen, hydroxy, keto, C₁ -C₁₈ alkyloxy, aryloxy and amino; and R4and R5 individually are selected from the group consisting of C₁ -C₁₈alkyl, aryl, halo and trifluoroalkyl.
 7. The method of claim 1 whereinsaid compound is a compound of the formula: ##STR30## wherein R1 isselected from the group consisting of hydroxyl, ##STR31## wherein R6, R7and R8 are individually a C₁ -C₂₀ straight chain aliphatic radical, C₁-C₂₀ branched chain aliphatic radical or C₃ -C₂₀ cyclic aliphaticradical, or aromatic radical, or a heterocyclic radical selected fromthe group consisting of 1-methyl-1,4-dihydronicotinoyl, piperidinyl,pyridinyl, furanyl, thiophenyl, and pyrazinyl, and Y is --O-- or--S--;R2 is a moiety of the formula ##STR32## wherein R17 and R18individually are a C₁ -C₂₀ straight chain aliphatic radical, C₁ -C₂₀branched chain aliphatic radical or C₃ -C₂₀ aliphatic radical, oraromatic radical, or a heterocyclic radical selected from the groupconsisting of 1-methyl-1,4-dihydronicotinoyl, piperidinyl, pyridinyl,furanyl, thiophenyl, and pyrazinyl and R19 and R20 are individuallyhydrogen or a C₁ -C₂₀ straight chain aliphatic radical, C₁ -C₂₀ branchedchain aliphatic radical or C₃ -C₂₀ cyclic aliphatic radical, or aromaticradical, or a heterocyclic radical selected from the group consisting of1-methyl-1,4-dihydronicotinoyl, piperidinyl, pyridinyl, furanyl,thiophenyl, and pyrazinyl or ##STR33## wherein R21 is H or a C₁ -C₂₀straight chain aliphatic radical, C₁ -C₂₀ branched chain aliphaticradical or C₃ -C₂₀ cyclic aliphatic radical, or aromatic radical, or aheterocyclic radical selected from the group consisting of1-methyl-1,4-dihydronicotinoyl, piperidinyl, pyridinyl, furanyl,thiophenyl, and pyrazinyl; R3 is selected from the group consisting ofhydrogen, hydroxy, keto, C₁ -C₁₈ alkyloxy, aryloxy and amino; R4 isselected from the group consisting of alkyl, aryl, halo, andtrifluoroalkyl; and R5 is selected from the group consisting of alkyl,aryl, halo, and trifluoroalkyl.
 8. The method of claim 1 wherein saidcompound is a compound of the formula: ##STR34## wherein R1 is hydroxy;R2 is a member selected from the group consisting of acetyl,2-hydroxyethanonyl, and 1-hydroxyethyl;R3 is hydrogen; and R4 and R5 areeach methyl.
 9. The method of claim 1 wherein said pharmaceuticallyeffective amount is from about 50 mg to about 500 mg per dosage unit.10. A compound of the formula: ##STR35## wherein R1 is selected from thegroup consisting of hydroxy, ##STR36## wherein R6, R7 and R8 areindividually a C₁ -C₂₀ straight chain aliphatic radical, C₁ -C₂₀branched chain aliphatic radical or C₃ -C₂₀ cyclic aliphatic radical, oraromatic radical, or a heterocyclic radical selected from the groupconsisting of 1-methyl-1,4-dihydronicotinoyl, piperidinyl, pyridinyl,furanyl, thiophenyl, and pyrazinyl, and Y is --O-- or --S--;R2 isselected from the group consisting of ##STR37## wherein R9, R10, R11,R12, R13, R14, R17, R18, R19 and R20 are individually a C₁ -C₂₀ straightchain aliphatic radical, C₁ -C₂₀ branched chain aliphatic radical or C₃-C₂₀ cyclic aliphatic radical, or aromatic radical, or a heterocyclicradical selected from the group consisting of1-methyl-1,4-dihydronicotinoyl, piperidinyl, pyridinyl, furanyl,thiophenyl, and pyrazinyl with the provisos that(1) R9, R10 and R11 mayalso individually be an amide ##STR38## radical wherein R15 and R16individually are a C₁ -C₂₀ straight chain aliphatic radical, C₁ -C₂₀branched chain aliphatic radical or C₃ -C₂₀ cyclic aliphatic radical, oraromatic radical, or a heterocyclic radical selected from the groupconsisting of 1-methyl-1,4-dihydronicotinoyl, piperidinyl, pyridinyl,furanyl, thiophenyl, and pyrazinyl, and n=1 to 8 and (2) R19 and R20 mayalso individually be H or ##STR39## wherein R21 is H or a C₁ -C₂₀straight chain aliphatic radical, C₁ -C₂₀ branched chain aliphaticradical or C₃ -C₂₀ cyclic aliphatic radical, or aromatic radical, or aheterocyclic radical selected from the group consisting ob1-methyl-1,4-dihydronicotinoyl, piperidinyl, pyridinyl, furanyl,thiophenyl, and pyrazinyl, and n is an integer of 1 to 8; R3 is selectedfrom the group consisting of hydrogen, hydroxy, keto, C₁ -C₁₈ alkyloxy,aryloxy and amino; and R4 and R5 individually are selected from thegroup consisting of C₁ -C₁₈ alkyl, aryl, halo and trifluoroalkyl. 11.The method of claim 7 wherein R4 is C₁ -C₁₈ alkyl.
 12. The method ofclaim 7 wherein R5 is C₁ C₁₈ alkyl.